Acute lung injury (ALI) is a fatal complication of influenza infections. In particular, the elderly is a population at risk of increase morbidity and mortality from influenza infection. A critical mediator of ALI is transforming growth factor beta (TGF-β), which can be activated directly by influenza virus. ALI is characterized by three phases: i) In the exudative phase there is an increase in alveolar-capillary permeability, increase inflammatory markers in the bronchoalveolar lavage fluid (BALF) and impairment of lung compliance. Impairment of the alveolar epithelial barrier by disruption of cell adhesion proteins is an important mechanism during this phase. ii) In the fibroproliferative phase there is increase collagen deposition and lung fibrosis. iii) In the resolution phase, proliferation and differentiation of lung progenitor cells play a role in lung repair mechanisms.
ALI includes Acute Respiratory Distress Syndrome (ARDS) and also milder forms of lung injury. ARDS is a sudden failure of the respiratory system, characterized by widespread inflammation of the lung that leads to fluid leaking into the alveoli, impairing gas exchange. It is associated with pulmonary cytokine release, impaired endothelial barriers, fluid accumulation in distal airspaces, and fibrotic changes. ARDS is a clinical syndrome characterized by hypoxemia, bilateral lung infiltrates, and normal wedge pressure. Approximately 250,000 Americans develop ALI annually (Goss, Christopher H., et al. “Incidence of acute lung injury in the United States.” Critical care medicine 31.6 (2003): 1607-1611). Approximately 190,000 Americans develop ARDS annually (http://www.lung.org/lung-disease/acute-respiratory-distress-syndrome/understanding-ards.html). An estimated 132,000 people in the US have pulmonary fibrosis, with many more having some form of interstitial lung disease. All of these diseases harm lung tissue.
The primary causes of ARDS/ALI are sepsis (infection of the bloodstream), inhalation of harmful substances, severe pneumonia, and viral infections that affect the lungs (influenza, MERS, SARS, Ebola, Hunta Virus, etc.). The only current treatment of ARDS/ALI is lung protective ventilation. Despite recent improvements in ventilation strategies, ARDS mortality continues to be close to 40%. If ventilation is not successful, a lung transplant is necessary. There are currently no medications that repair lung tissue. Therefore, there is a critical need to develop novel and effective therapies for patients with ALI, and especially in patients with influenza induced ALI.